Geography-independent mucosal microbiota alterations in primary sclerosing cholangitis persist after liver transplantation

<h2>Abstract</h2><h3>Background and Aims</h3> PSC-associated alteration of fecal gut microbiota has already been described, but data on the mucosal microbiota are still limited. We aimed to further define disease-specific mucosal microbial patterns independent of geography and assess the relationship to liver transplantation (LTx), gut inflammation (IBD), and PSC recurrence (rPSC). <h3>Methods</h3> Sequencing of the 16S ribosomal RNA gene (V3–V4) from ileocolonic biopsies was performed on 115 PSC (pre_LTx), 159 liver-transplanted (post_LTx, 38 of them developed recurrence), and 96 healthy controls (HC) from Norway and the Czech Republic. <h3>Results</h3> Alpha diversity was lower in all PSC groups than in HC. An elastic net model discriminated well both pre_LTx (AUC ileum 0.97; colon 0.93; p<0.001) and post_LTx PSC patients (AUC ileum 0.97; colon 0.97; p<0.001) from HC, and also between pre_LTx and post_LTx (AUC ileum 0.83; colon 0.83; p<0.001). The shared cohort-independent PSC microbiota was dominated by <i>Enterococcus, Pseudomonas, Veillonella, Klebsiella</i>, and <i>Streptococcus</i>, while some common commensals were underrepresented. A Microbial Dysbiosis Index calculated from PSC-associated genera correlated negatively with alpha diversity and serum albumin, while a positive correlation was observed with markers of cholestatic disease (ALP, GGT) and liver fibrosis (APRI). There were no associations with the presence of IBD or correlation with fecal calprotectin. There were limited differences between post_LTx with and without recurrence, but several genera deregulated in pre_LTx PSC (<i>Klebsiella, Bilophila, Coprococcus, Odoribacter)</i> had a similar trend in rPSC. <h3>Conclusions</h3> Our findings in two European countries revealed a distinct mucosal microbiota composition associated with PSC that persists after LTx. This correlated with the severity of PSC liver injury but not with markers of intestinal inflammation. <h3>Impact and implications</h3> This study provides an extensive evaluation of mucosa-associated microbiota in PSC before and after liver transplantation across two European cohorts. The persistence of PSC-related dysbiosis after transplantation highlights the importance of the gut–liver axis in PSC and supports further investigation into microbiota-driven mechanisms. Together with a strong association between microbiota composition and markers of cholestasis and fibrosis it suggests potential clinical utility as indicator of disease activity or even as target for prevention or therapy.